P38γ MAPK is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion

Xiaomei Qi, Ning Yin, Shao Ma, Adrienne Lepp, Jun Tang, Weiqing Jing, Bryon Johnson, Michael B. Dwinell, Christopher R. Chitambar, Guan Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Triple-negative breast cancer (TNBC) is highly progressive and lacks established therapeutic targets. p38γ mitogen-activated protein kinase (MAPK) (gene name: MAPK12) is overexpressed in TNBC but how overexpressed p38γ contributes to TNBC remains unknown. Here, we show that p38γ activation promotes TNBC development and progression by stimulating cancer stem-like cell (CSC) expansion and may serve as a novel therapeutic target. p38γ silencing in TNBC cells reduces mammosphere formation and decreases expression levels of CSC drivers including Nanog, Oct3/4, and Sox2. Moreover, p38γ MAPK-forced expression alone is sufficient to stimulate CSC expansion and to induce epithelial cell transformation in vitro and in vivo. Furthermore, p38γ depends on its activity to stimulate CSC expansion and breast cancer progression, indicating a therapeutic opportunity by application of its pharmacological inhibitor. Indeed, the non-toxic p38γ specific pharmacological inhibitor pirfenidone selectively inhibits TNBC growth in vitro and/or in vivo and significantly decreases the CSC population. Mechanistically, p38γ stimulates Nanog transcription through c-Jun/AP-1 via a multi-protein complex formation. These results together demonstrate that p38γ can drive TNBC development and progression and may be a novel therapeutic target for TNBC by stimulating CSC expansion. Inhibiting p38γ activity with pirfenidone may be a novel strategy for the treatment of TNBC.

Original languageEnglish (US)
Pages (from-to)2738-2747
Number of pages10
JournalStem Cells
Issue number9
StatePublished - Sep 1 2015


  • Cancer stem-like cells
  • Therapeutic target
  • Triple negative breast cancer
  • c-Jun/AP-1
  • p38γ MAPK

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology
  • Developmental Biology


Dive into the research topics of 'P38γ MAPK is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion'. Together they form a unique fingerprint.

Cite this